Premature ovarian failure (POF) afflicts 1-2% of women, and genetics contributes as much as 70% to POF. Most cases of ovarian failure are sporadic due to associated infertility. POF in the vast majority of women is non-syndromic, i.e., it only affects ovarian function. Mutations in few genes preferentially expressed in the ovary, such as follicle stimulating hormone receptor (FSHR) and bone morphogenetic protein 15 (BMP15), have been functionally shown to afflict some women with POF. Over the past decade a number of genes preferentially expressed in oocytes have been discovered. Mouse studies have led the way in identifying genes preferentially expressed in oocytes, because human oocytes are difficult to obtain and study. Mouse knockouts, generated mainly by our laboratory, show that transcriptional regulators Nobox, Sohlh1 and Figla, are preferentially expressed in the germline and cause ovarian failure in mice. Over the past 2 years, we have enrolled women with sporadic and familial POF to determine the genetics of human ovarian failure. We have enrolled over 100 women and continue to enroll more subjects. Our preliminary data show that mutations in NOBOX and FIGLA can cause human ovarian failure. Therefore, genes preferentially expressed in oocytes represent ideal candidates for genetic causes of POF. We identified ten candidate genes preferentially expressed in mouse oocytes that are conserved in humans and belong to the pathway regulated by NOBOX and FIGLA. We hypothesize that profiling the coding and regulatory sequences of these ten genes preferentially expressed in oocytes will reveal novel mutations and patterns of common allelic variants that lead to ovarian failure. In addition, we will utilize oligonucleotide array comparative genomic hybridization to identify copy number variants that associate with ovarian failure. PUBLIC HEALTH RELEVANCE: Ovarian failure adversely affects women's reproductive potential, psychosocial well-being, bone mineralization, cardiovascular health and life span. We propose to determine genetic etiology of human ovarian failure through analyses of mutations in oocyte-specific genes and structural changes in the genome. Identification of novel genetic markers for human ovarian failure will help identify women at risk for increased medical morbidity and mortality as well as offer them earlier medical interventions to preserve their reproductive options.